Side effects of the CB1 receptor inverse agonist/antagonist, rimonabant (SR141716; SR), in humans include nausea and depression (de Mattos Viana et al., 2009; Despres, 2009). The nausea produced by SR and another compound AM251 (McLaughlin et al., 2005) is the result of the inverse agonism at the CB1 receptor (Sink et al., 2008). Equivalent doses of AM251 produced conditioned gaping in rats.
The conditioned gaping model (see Parker et al., 2008 for review) has been shown to detect the nauseating side effect of several compounds, including selective serotonin reuptake inhibitors (SSRIs), phosphodiesterase-4 inhibitors and CB1 receptor inverse agonists (McLaughlin et al., 2005; Sink et al., 2008).
As well as producing nausea on their own, the CB1 receptor inverse agonists (at sub-threshold doses that do not produce nausea on their own), SR (Parker et al., 2003) and AM251 (Limebeer et al., 2010), potentiate the nausea produced by the toxin lithium chloride (LiCl).
Phytocannabinoids have recently become candidates for therapeutic applications, however their usefulness may be limited if they exhibit nausea producing effects. Much of the research on phytocannabinoids has concentrated on the psychoactive compound, THC and, the primary non-psychoactive cannabinoid, cannabidiol (CBD), found in marijuana. Low doses (0.5 mg/kg THC and 5 mg/kg CBD) of both of these compounds have been shown to suppress toxin-induced conditioned gaping in the rodent model of conditioned nausea (Limebeer & Parker 1999; Parker et al., 2002; Parker et al., 2003).
The effects of phytocannabinoid tetrahydrocannabivarin (THCV) in the rodent model of conditioned nausea were unknown.
Recent work with both plant-derived THCV and synthetic THCV (0-4394) has elucidated its behavioural effects and mechanism of action. In vitro, THCV acts as a CB1 and CB2 receptor antagonist (Thomas et al., 2005).
In vivo, THCV has also been shown to act as a CB1 receptor antagonist at low doses (<3 mg/kg) (Pertwee et al., 2007). THCV shares the ability of AM251 to reduce the food intake and body weight of non-fasted and fasted mice (Robinson et al., 2007).
THCV has been shown to suppress seizure activity (Hill et al., 2010), reduce inflammation and inflammatory pain (Bolognini et al., 2010), reduce weight due to hypophagia (Riedel et al., 2009), it is also able to reduce Parkinson's disease symptoms, as well as disease progression (Garcia et al., 2011). Therefore, further examination of potential nauseating side effects of THCV is important.
The patent GB2384707B describes the anti-emetic effect of CBD and CBDA using the suncus murinus model of nausea.
The applicants have evaluated whether the phytocannabinoid produced nausea and potentiate toxin-induced nausea. Because it is known that THCV can behave as a CB1 antagonist and shares the ability of SR and AM251 to reduce food intake in vivo it was likely that this phytocannabinoid would produce nausea and potentiate toxin-induced nausea.
Surprisingly the applicants have discovered that THCV neither produced nausea nor potentiated toxin-induced nausea and more significantly at high doses actually acted as an anti-emetic. As such THCV is a potential candidate for use in the treatment of nausea and vomiting.